Understanding the Cytokine Release Syndrome: toward Improving Cancer Immunotherapy

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Background

Chimeric antigen receptor (CAR)-T cell immunotherapy, based on the infusion of genetically modified autologous T cells to recognize an antigen expressed on the tumor cell, has arisen in the last years as a new strategy to treat cancer patients. In B-cell hematological malignancies the administration of CART cells has achieved outstanding responses leading to the FDA approval of two of these living drugs in 2017. Along with these remarkable results, come novel toxicities after CART cell administration, including the occurrence of immune-related adverse events (irAE's) cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) in a subset of patients. Regarding these toxicities, a variety of pro-inflammatory cytokines are detected after a few hours of CART/tumor cell-cell contact and activation. However, it is intriguing to consider the existence of other pro-inflammatory molecules secreted at earlier time points that could be acting as initiators of the CRS development. This inflammatory secretome can be a double-edged sword in cancer treatment. Although pro-inflammatory mediators such as ROS, FAS, CRP, TNF, IL-1β, and IL-6, can activate the anti-tumor immune response, in the event that CART cells do not achieve the eradication of tumor cells, these soluble molecules could also provide a favorable microenvironment for the exponential growth of malignant cells.

In addition, during this continuous cross-talk between CAR T cells and tumor cells, other surrounding immune cells, such as macrophages, release factors responsible for the development of tumor cell resistance mechanisms jeopardizing CART cell activity. Most studies on CART cell therapies have focused on the direct activity mediated by CART cells against tumor cells. However, the molecular mechanisms controlled by the vast range of secreted factors upon tumor-CART cell interaction remain poorly understood. Since changes in secretome will impact the CRS development and the development of tumor cell resistance mechanisms against CART cells, we propose to focus on this line of research to better understand this crucial aspect of the anti-tumor immunity and toxicity.

In an attempt to develop optimized CART cell immunotherapy treatments for hematologic and solid tumors, we encourage authors to submit Original Research and Review articles that explore:

i) identification of new soluble factors and tumor proteins secreted after CART/tumor cell contact;
ii) their roles in modulating CART anti-tumor activity, inflammatory response, and development of toxicity or tumor cell resistance mechanisms;
iii) functional studies to evaluate whether these pro-inflammatory mediators can be blocked without impacting on CART cell activity.

Important note: All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.

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